The present invention relates to novel chemical compounds, to methods for synthesis of such compounds, and to the use of these novel compounds in the synthesis of other chemical compounds that, among other things, can be used in the treatment of sexual dysfunction, and for eliciting enhancing effects on sexual behavior. The invention also relates to remarkable biological properties of the novel compounds in their capacity of inducing aggressive behavior.
The previous application WO 2008/145996 described compounds with sexual enhancing activity having the general structure (1):

(i.e. structure III in WO 2008/145969; for substituents see substituents for structure III in WO 2008/145996; note that R15, R5, and R12 in (1) is, respectively, R1, R4 and R5 in WO 2009/145996; note however that for the present patent any reference to substituent or atom numbering does not refer to WO 2009/145996; rather they refer only to the substituent and atom numberings defined herein). WO 2008/145996 claimed the use of compound (1) for the treatment of sexual dysfunctions, such as erectile dysfunction.
However, compounds of structure (1) have hitherto been found only in some plants, and appear there to be rare; only a few representatives of (1) have been found among a few species of the Meliaceae family, where they are present in only small quantities (WO 2008/145996; Luo et al., 2009; see also below). These compounds are therefore difficult and expensive to isolate in any amounts of practical utility, e.g. for use as remedies for treatment of disease.
Working out the full synthesis of a compound according to (1) is a very difficult undertaking indeed, and has not been attempted thus far. However, structures according to the general formula (2a):

wherein, the substituents R1 to R9 vary to a great deal, and where covalent bonds between R1 and R9, and R8 and R9 (marked as hatched lines) (and even between R2 and R3, R3 and R4, and R7 and R8) may or may not be present, are found ubiquitously in nature, where they constitute members of a class of compounds which generally is termed limonoids. Limonoids are particularly found among species of the Meliaceae, often in high quantities in woods, barks or seeds, and methods to isolate them are well known in the art.
Limonoids (2a) include, for example, compounds with the given names xyloccensin E (Connolly et al. 1976; Sarigaputi et al. 2010), xylocarpin I (Cui et al. 2007), kotschyins (Hay et al. 2007), phragmalins (Arndt et al. 1972; Connolly et al. 1978; Nakatani et al. 2004), swietenialides (Saad et al 2003), neobeguins (Randrianarivelojosia et al 1999), pseudrelones (Ekong and Olagbemi, 1967; Mulholland and Taylor 1988; Niven and Taylor 1988), busseins (Guex and Tamm 1984; Taylor 1967), chukrasins (Ragettli et al. 1978; Brown and Taylor 1978), tabulalides (Nakatani et al. 2004). See also Mulholland et al. 2000, and Narender et al. 2008 for compounds included among compounds with structure (2a).
Moreover, among compounds with CAS (Chemical Abstracts Service, at 2540 Olenstangy River Road, Columbus, Ohio 43202, USA) Registry numbers 1299464-67-7, 1267877-55-3, 1248571-24-5, 1219132-70-3, 1214981-83-5, 1214976-20-1, 1186131-42-9, 1126643-44-4, 1126643-43-3, 1126643-42-2, 1053209-52-1, 1045017-87-5, 1038746-45-0, 952615-91-7, 910578-31-3, 803723-28-6, 803723-27-5, 561307-83-3, 260794-07-8, 116408-24-3, 115391-10-1, 115367-50-5, 98401-23-1, 98379-64-7, 98379-62-5, 98379-61-4, 98379-60-3, 98379-59-0, 98379-58-9, 98379-57-8, 96386-37-7, 90955-39-8, 90931-03-6, 90931-02-5, 90931-01-4, 90931-00-3, 90930-99-7, 90930-98-6, 90930-97-5, 90930-96-4, 90930-95-3, 81584-75-0, 67931-05-9, 67931-04-8, 67904-58-9, 67904-57-8, 67904-56-7, 67904-55-6, 67904-54-5, 67904-53-4, 67895-40-3, 67895-39-0, 67895-38-9, 66939-94-4, 66901-32-4, 66901-31-3, 66901-30-2, 66884-81-9, 66884-80-8, 66884-79-5, 66884-78-4, 66884-77-3, 66495-42-9, 66451-22-7, 52724-62-6, 52681-81-9, 41508-26-3, 41060-14-4, 41060-13-3, 40185-37-3, 40185-36-2, 40185-34-0, 40185-33-9, 38575-45-0, 37832-02-3, 37665-93-3, 37665-92-2, 37665-91-1, 37665-90-0, 35183-64-3, 35055-81-3, 939775-81-2, structures of type (2a) are found.
Further more structures according to the general formula (2b) also exist in nature:

wherein in (2b) R12 may often be —O—R10, or oxo, and wherein the substituents R1 to R12 vary to a great deal, and where covalent bonds between R1 and R9, and R8 and R9 (marked as hatched lines in 2a and 2b) (and even between R2 and R3, R3 and R4, and R7 and R8) may or may not be present, where they are also found to some extent among species of the Meliaceae family, albeit generally in comparatively much smaller amounts in the various plant tissues, compared to those for (2a).
Compounds (2b) include the leandreanin A and B, isolated from Neobeguea leandreana (Coombes et al.: J Nat Prod. 2003, 66(6):735-8.), kotschyins A, B and C, isolated from Pseudocedrela kotschyi (Hay et al.: J Nat Prod. 2007 January; 70(1):9-13.), phragmalin compounds listed as no. 1, 2, 3, 6 and 7 on page 80 in Piaz et al. (Piaz et al.; Phytochemistry. 2012, 75:78-89), ring opened phragmalins isolated from Swietenia macrophyla (Lin et al. J Nat Prod. 2009, 72(7):1305-13), Swietenia mahogany (Saad et al. Tetrahedron 2003, 59, 8027-8033) and Carapa guianensis (Tanaka et al.: Tetrahedron 2012, 68, 3669-3677).
Compounds (2b) also include compounds with CAS Registry numbers 1173892-10-8, 1173892-09-5, 1173892-08-4, 1173892-07-3, 1173892-06-2, 1173892-05-1, 1173892-04-0, 1173892-03-9, 1169770-19-7, 1169770-18-6, 1169770-17-5, 1159493-38-5, 1159493-37-4, 1159493-36-3, 1159493-35-2, 1159493-34-1, 1159493-33-0, 1088920-97-1, 1088920-95-9, 1088920-93-7, 1088920-91-5, 1088920-89-1, 1088920-87-9, 1088920-85-7, 1088920-83-5, 1088920-81-3, 1088920-69-7, 1088920-67-5, 1088920-65-3, 1088920-63-1, 1088920-61-9, 1088920-59-5, 1088920-57-3, 1088920-55-1, 1088920-53-9, 1088920-51-7, 1088920-49-3, 1088920-47-1, 1088920-44-8, 1088920-42-6, 629654-42-8, 629654-41-7, 926896-45-9, 926896-45-9.
(Hereinafter, the structures (2a) and (2b) are collectively referred to as “structure (2)”. [Note also that the above numbering of the atoms in the skeleton of compound (2a) and (2b) apply throughout this patent also for the corresponding atoms in anyone of compounds (1), (2aa), (2bb), (3), (3a), (4), (4aa), (4bb), (4cc), (4dd), (4ee), (4ff), (4gg), (4hh), (5) and (5a) (listed compounds defined further below and in the amended claims), phragmalin, or compound with the corresponding phragmalin skeleton of this patent and in WO 2008/145996.]
Therefore, structures (2a) and (2b) confine potential starting materials for affording structure (1) [or for obtaining the even more general structure (5); see below] by semi-synthesis, a field that was the subject of our interest for some time. However, due to the fact that compounds with structure (2b) are less ubiquitous in nature and there known to be available only in only small amounts per weight of plant tissues of distinct species, structure (2b) is not particularly useful for the sake of the present invention, which aims for a highly efficient process for synthesis of compound (1), (5) and (5a). Compounds with structure (2b) [including (2bb)] are therefore for essentially all embodiments of the present invention for practical reasons excluded as starting material for synthesis of a compound (1) [and even for synthesis of (2b), (2bb), (3), (3a), (4), (4aa), (4bb), (4cc), (4dd), (4ee), (4ff), (4gg), (4hh), (5) and (5a); see below] by the process of the invention aiming for high yield synthesis.
However, specifically in synthesis of (1) [and even (5) and (5a)] affording a route for opening the lactone ring in (2a) and closing it into the lactone of (1) proved to be a vast more difficult task than expected and failed using many commonly applied methods for ring opening and closing. This included hydrolytic ring opening of compounds of structure (2a) (e.g. using 0.1 M potassium hydroxide in methanol or 0.1 M sodium hydroxide in water), which were not successful as many side products formed, and the expected carboxylates/their salts could not consistently be demonstrated with NMR analysis. Moreover, adjustment of pH of the reaction mixture led to re-lactonization of the eventually opened lactone ring, providing the starting compound but not the desired products of anyone of structures (1), (5) or (5a). Moreover, the high polarity of carboxylates as the attempted intermediates made monitoring of reactions and isolation of the products difficult, as well as the carboxylate salts formed limited the choice of solvents for oxidation-reactions to afford the most desired oxidation of the hydroxy group at carbon 17 following the ring opening [for atom numbering see structures (2a) and (2b)] prior to closing the lactone in the desired position. Over all these problems rendered the approach of hydrolytic ring opening of a compound (2a) for affording structures (1), (5) and (5a) useless.
Attempts to reductive openings of the lactone ring in compound (2a) were also unsuccessful. Thus, attempts to open the ring in O-protected phragmalins with diisobutylaluminium hydride (DIBAL-H), lithium aluminium hydride (LAH) essentially using procedures as in Bloomfield and Lee, 1967 and Pettit G R et al., 1962, or sodium bis(2-methoxyethoxy)aluminiumhydride (Red-Al) and lithium borohydride (LiBH4) resulted all in complex mixtures (presumably due to stability issues of the ortho-ester functionality), which also rendered these approaches useless.
In addition several attempts on amidolytic ring opening of the lactone in compound (2a) failed. Thus thermal aminolysis with NH3 in methanol at temperatures from 20 to 90° C., essentially using procedures as in Yi et al. 2005, as well as trimethyl aluminium (Me3Al) promoted aminolysis with benzylamine in dichloromethane, essentially using procedures as in Liu et al. 2001, both failed in producing a product with opened ring.
However, this patent solves the problem of opening the lactone ring in a compound of structure (2a) and closing it in another position to provide a compound with structure (1), as well as how to provide a compound with structure (5) and (5a), and the compound of claim 40 [i.e. general structure (III)] in WO 2008/145996. However, the process required surprisingly distinct conditions and distinct reagents to proceed at all, while other closely similar conditions to the successful one led to the excessive formation non-desired side products without formation of any desired product at all. Accordingly the narrow range of suited conditions were indeed not foreseeable by prior art, but are disclosed in this patent. On top of this, for the most preferred embodiments of the invention [i.e. in particular those embodiments which used the most desired starting materials with structure (2a) to yield the most desired end products with structures (1), (5) and (5a)], the patent provides solutions for achieving a) chemoselectivity and regioselectivity between chemically similar groups (e.g. lactone versus ester in formation of the specific Weinreb amide required in the process), b) regioselectivity between two or three secondary hydroxy groups for affording desired chemical reactions required in the process, and c) the appropriate protection of chemical groups to avoid unwarranted side reactions, all parts, a), b) and c), which were necessary and achieved by the processes of the invention in a surprising way (on top of the above mentioned surprisingly distinct conditions and distinct reagents required for the process to proceed at all) that would be impossible to foresee from prior art by anyone skilled in the art.
On top of this the patent provides a highly efficient process for the manufacture of a compound with structure (5), (5a), (1) or the compound of claim 40 [i.e. general structure (III)] in WO 2008/145996, from raw-materials which are possible to afford in large quantities; the disclosed process being markedly more efficient (i.e. in terms of yield of starting material) than any earlier reported processes for the provision of such compounds.
On top this, the process of this patent provides a direct way to afford a compound of structure (2b) from a compound of structure (2a). This is also a highly important embodiment of the invention, as compounds of structure (2b) have industrial and medical applicability; the unity inventive steps for this aspect of the invention being the same as for converting the compound (2a) or (2b) to a compound with structure (1), (5) and (5a).
On top of this, this patent provides a novel compound (3) [including the more specific structures (3a), (4), (4aa), (4bb), (4cc), (4dd), (4ee), (4ff), (4gg) and (4hh) confined in (3)], including an efficient process to obtain these compounds in high yield, which is in fact the key inventive step in the processes disclosed herein for synthesis of compound (5) [including synthesis of the more specific structure (1) and (5a) confined in (5) and those of claim 40 in WO 2008/145996 also confined in (5)], as well as in synthesis of (2b). Moreover on top of this compound (3) was totally unexpectedly and extremely surprising found to induce marked aggressive behavior when administered to a mammal, a feature that renders compound (3) further highly useful; all aspects and uses of compound (3) are disclosed herein.